Discovery of Polycyclic Polyprenylated Acylphloroglucinols from Hypericum androsaemum as Dual-Mechanism Inhibitors of Mycobacterium tuberculosis GlmU Acetyltransferase
Abstract
(±)-Hypericandrone A (HCA, 1), an unprecedented pair of enantiomeric polycyclic polyprenylated acylphloroglucinols (PPAPs), and its biosynthetic congener hypericandrone B (HCB, 2) were isolated from the fruits of Hypericum androsaemum. Compound 1 features a unique 2-cyclopentane-bicyclo[3.3.0]octane scaffold, while 2 possesses a rare 2-cyclopentyltetrahydrofuran framework. Their absolute configurations were unequivocally determined by spectroscopic analysis, single-crystal X-ray diffraction, and ECD calculations. Remarkably, (+)-1 displayed potent antitubercular activity by selectively inhibiting the acetyltransferase domain of Mycobacterium tuberculosis GlmU through a dual mechanism, acting competitively against acetyl-CoA (Ki = 0.07 μM) and noncompetitively against glucosamine-1-phosphate (GlcN-1-P, Ki = 0.20 μM).
Fields of Study & Subjects
Natural Compound Pharmacology Studies
Bioactive natural compounds
Carbohydrate Chemistry and Synthesis
Publication details
- Journal / source
- Organic Letters
- Publisher
- American Chemical Society (ACS)
- Volume
- 28
- Issue
- 32
- Pages
- 10296–10301
- Publication date
- 3 August 2026
- Language
- EN